In mice, as in humans, there are inherited disorders of the retina that cause blindness. Mouse retinal degeneration slow (rds) is one such disorder. This mutation has the phenotype of photoreceptor outer segment non-development, followed by slow degeneration of the photoreceptor cell bodies. Cloning of the rds gene during the first funding period directly lead to the demonstration that mutations in the human locus are responsible for several inherited retinal dystrophies including a subset of retinitis pigmentosa. The rds gene was found to encode an outer segment disc membrane glycoprotein of unknown function. The first aim of the present proposal is to determine the function of the rds protein, and to learn how its absence in rds/rds mutant mice causes dysplasia of rod and cone photoreceptors. This will be done with an integrated set of experiments employing biochemical, cell biological and genetic approaches. These experiments test the hypothesis that the rds protein is a member of a new class of adhesion molecule, and functions to stabilize outer segment discs through a heterophilic interaction with the related protein, rom-1. In addition to providing new information about the interesting process of photo receptor outer segment assembly, these experiments will potentially elucidate the molecular mechanisms of the human retinal dystrophies associated with mutations in the RDS gene. There are two other recessive photo receptor degeneration mutants of mouse where nothing is known about the underlying biochemical defect: Purkinje cell degeneration (pcd) and nervous (nr). The second aim of this proposal is to clone the gene for these two mutations, using a strategy based upon the techniques of differential RNA display and subtractive cDNA cloning. Candidate clones from these initial screens will be evaluated by chromosomal sub-localization using mouse inter- and intra-specific backcross panels. The most interesting aspect of this specific aim will be to identify the proteins encoded by the pcd and nr genes, and to learn how their functional loss results in the mutant phenotypes.